1,4-benzothiazepine derivatives

Details 1,4-benzothiazepine derivatives 1,4-benzothiazepine derivatives

1993-06-25

1995-05-16

Berch, Mark L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

540490, C07D41706, C07D41714, A61K 3155

Patent

active

054160669

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP91/01804.


TECHNICAL FIELD

This invention relates to novel 1,4-benzothiazepine derivatives, in particular novel 1,4-benzothiazepine derivatives having an effect of inhibiting overcontraction and overextension of the myocardium and protecting against myocardial necrosis without being accompanied by a cardiodepressant effect.
In addition, this invention relates to drugs containing the aforementioned novel 1,4-benzothiazepine derivatives as an effective ingredient which work on the circulatory system, in particular the 1,4-benzothiazepine derivatives containing the novel 1,4-benzothiazepine derivatives as an effective ingredient, which have an effect of inhibiting overcontraction and overextension of myocardium and protecting against myocardial necrosis without being accompanied by a cardiodepressant effect.


PRIOR ART

The recent increase in the average age of the population has been accompanied by an increase in circulatory diseases, such as hypertension, angina and myocardial infarction. In particular, there have been many sudden occurrences of myocardial infarction with a high mortality rate. Hitherto, the cause of this myocardial infarction has been attributed to obstruction, by thrombus or coronary spasm, of the coronary artery which supplies nutrition to the heart. Recently, however, Kaneko et al. have proposed a new mechanism for myocardial infarction, according to which the myocardia of myocardial infarction patients exhibit two forms of necrosis, Static Cell Death (hereinafter referred to as SD) and Kinetic Cell Death (hereinafter referred to as KD), with KD being the main cause of myocardial infarction (Journal of Tokyo Women's Medical College, 52, 1443, 1982). In addition, Kaneko et al. have reported using a rabbit to create a model of a myocardial infarction caused by KD, and using calcium antagonists to inhibit the symptoms thereof (refer to Japanese Patent Publication No. Sho 61-40651). Moreover, they have recently succeeded in creating a model of a myocardial infarction caused by KD in a Langendorff in vitro system using an isolated rat heart, and by using this model they have found that some Ca antagonists have a KD-inhibiting effect similar to that found the in vivo system. However, some of these Ca antagonists have a strong cardiodepressant effect, and it was thought desirable to develop compounds having a weak cardiodepressant effect, and a strong KD-inhibiting effect.


DISCLOSURE OF THE INVENTION

It is an object of this invention to provide compounds having a KD-inhibiting effect without being accompanied by a cardiodepressant effect and novel 1,4-benzothiazepine derivatives, in particular novel 1,4-benzothiazepine derivatives having specific substituent groups and pharmaceutically acceptable salts thereof.
In addition, it is an object of this invention to provide drugs for the prevention of myocardial necrosis and for the prevention and treatment of acute myocardial infarction in which the above-mentioned novel 1,4-benzothiazepine derivatives having specific substituent groups and pharmaceutically acceptable salts thereof are contained as an effective ingredient.
The above object of this invention is accomplished by 1,4-benzothiazepine derivatives and pharmaceutically acceptable salts thereof.
Namely, the compounds of this invention are 1,4-benzothiazepine derivatives represented by the following Formula [I]: ##STR4## wherein each of substituent groups is defined as follows: R represents H or a C.sub.1 -C.sub.3 lower alkoxy group; X represents O or H.sub.2 ; n represents 1 or 2; R.sup.1 represents H, a substituted phenyl group wherein the substituent group is OH or a C.sub.1 -CH.sub.3 lower alkoxy group, ##STR5## a C.sub.1 -C.sub.3 lower alkoxy group or ##STR6## wherein R.sup.2 represents a C.sub.1 -C.sub.3 acyl group and ph represents a phenyl group, or pharmaceutically acceptable salts thereof.
The ability to produce a strong KD-inhibiting effect without being accompanied by a cardiodepressant effect is a new property discovered in the novel 1,4-

REFERENCES:
patent: 3794639 (1974-02-01), Krapcho et al.
patent: 5158947 (1992-10-01), Tatsuoka
patent: 5250679 (1993-10-01), Blackburn
Journal of Tokyo Women's Medical College, 52, 1443 (1982).
Czollner et al Chemical Abstracts, vol. 111, No. 11, Abstract No. 97194n (1988).
Krapcho et al Chemical Abstracts, vol. 68, No. 19, Abstract No. 87285X (1968).

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